Contextual predictors of self-management and independence trajectories in adolescents and young adults with spina bifida.

AIM: To examine socioeconomic, condition-related, and neuropsychological predictors of self-management trajectories in adolescents and young adults with spina bifida. METHOD: In this longitudinal study, participants completed the Adolescent/Young Adult Self-Management and Independence Scale interview. Socioeconomic status (SES), shunt status, lesion level, and executive functioning were assessed. Growth in self-management was estimated using linear mixed-effects models. RESULTS: Participants (n = 99) were aged 18 to 27 years. Approximately half (52.5%) were female and White; 15.2% were Black; and 32.3% Hispanic or Latino. Although none of the predictors were associated with growth in self-management from ages 18 to 27 years (p > 0.05), several factors were associated with the intercept at age 18 years for total self-management. Higher SES at baseline predicted a higher total self-management score at age 18 years (b = 0.03, standard error [SE] = 0.01; p < 0.001). On average, participants at age 18 years with a shunt scored lower than those without a shunt (b = -0.90, SE = 0.32; p = 0.01); those with a thoracic lesion scored lower than those with lower lesion levels (lumbar: b = -1.22, SE = 0.34; sacral: b = -1.20, SE = 0.36; p = 0.001 for both). Better parent-reported and teacher-reported executive functions predicted higher total self-management (metacognitive: b = -0.03, SE = 0.01; behavioral regulation: b = -0.04, SE = 0.01; p < 0.05 for both). INTERPRETATION: On average, all participants improved in self-management over time. Additionally, baseline superiority in self-management for adolescents and young adults without a shunt, less severe lesions, better executive functions, and higher SES persisted over time.

Evaluation of acoustic-thermal simulations of in vivo magnetic resonance guided focused ultrasound ablative therapy.

PURPOSE: To evaluate numerical simulations of focused ultrasound (FUS) with a rabbit model, comparing simulated heating characteristics with magnetic resonance temperature imaging (MRTI) data collected during in vivo treatment. METHODS: A rabbit model was treated with FUS sonications in the biceps femoris with 3D MRTI collected. Acoustic and thermal properties of the rabbit muscle were determined experimentally. Numerical models of the rabbits were created, and tissue-type-specific properties were assigned. FUS simulations were performed using both the hybrid angular spectrum (HAS) method and k-Wave. Simulated power deposition patterns were converted to temperature maps using a Pennes' bioheat equation-based thermal solver. Agreement of pressure between the simulation techniques and temperature between the simulation and experimental heating was evaluated. Contributions of scattering and absorption attenuation were considered. RESULTS: Simulated peak pressures derived using the HAS method exceeded the simulated peak pressures from k-Wave by 1.6 ± 2.7%. The location and FWHM of the peak pressure calculated from HAS and k-Wave showed good agreement. When muscle acoustic absorption value in the simulations was adjusted to approximately 54% of the measured attenuation, the average root-mean-squared error between simulated and experimental spatial-average temperature profiles was 0.046 ± 0.019 °C/W. Mean distance between simulated and experimental COTMs was 3.25 ± 1.37 mm. Transverse FWHMs of simulated sonications were smaller than in in vivo sonications. Longitudinal FWHMs were similar. CONCLUSIONS: Presented results demonstrate agreement between HAS and k-Wave simulations and that FUS simulations can accurately predict focal position and heating for in vivo applications in soft tissue.

Simultaneous proton resonance frequency T1 - MR shear wave elastography for MR-guided focused ultrasound multiparametric treatment monitoring.

PURPOSE: To develop an efficient MRI pulse sequence to simultaneously measure multiple parameters that have been shown to correlate with tissue nonviability following thermal therapies. METHODS: A 3D segmented EPI pulse sequence was used to simultaneously measure proton resonance frequency shift (PRFS) MR thermometry (MRT), T1 relaxation time, and shear wave velocity induced by focused ultrasound (FUS) push pulses. Experiments were performed in tissue mimicking gelatin phantoms and ex vivo bovine liver. Using a carefully designed FUS triggering scheme, a heating duty cycle of approximately 65% was achieved by interleaving FUS ablation pulses with FUS push pulses to induce shear waves in the tissue. RESULTS: In phantom studies, temperature increases measured with PRFS MRT and increases in T1 correlated with decreased shear wave velocity, consistent with material softening with increasing temperature. During ablation in ex vivo liver, temperature increase measured with PRFS MRT initially correlated with increasing T1 and decreasing shear wave velocity, and after tissue coagulation with decreasing T1 and increasing shear wave velocity. This is consistent with a previously described hysteresis in T1 versus PRFS curves and increased tissue stiffness with tissue coagulation. CONCLUSION: An efficient approach for simultaneous and dynamic measurements of PRSF, T1 , and shear wave velocity during treatment is presented. This approach holds promise for providing co-registered dynamic measures of multiple parameters, which correlates to tissue nonviability during and following thermal therapies, such as FUS.

A k-space-based method to measure and correct for temporal B0 field variations in MR temperature imaging.

PURPOSE: Present a method to use change in phase in repeated Cartesian k-space measurements to monitor the change in magnetic field for dynamic MR temperature imaging. METHODS: The method is applied to focused ultrasound heating experiments in a gelatin phantom and an ex vivo salt pork sample, without and with simulated respiratory motion. RESULTS: In each experiment, phase variations due to B0 field drift and respiration were readily apparent in the measured phase difference. With correction, the SD of the temperature over time was reduced from 0.18°C to 0.14°C (no breathing) and from 0.81°C to 0.22°C (with breathing) for the gelatin phantom, and from 0.68°C to 0.13°C (no breathing) and from 1.06°C to 0.17°C (with breathing) for the pork sample. The accuracy in nonheated regions, assessed as the RMS error deviation from 0°C, improved from 1.70°C to 1.11°C (no breathing) and from 4.73°C to 1.47°C (with breathing) for the gelatin phantom, and from 5.95°C to 0.88°C (no breathing) and from 13.40°C to 1.73°C (with breathing) for the pork sample. The correction did not affect the temperature measurement accuracy in the heated regions. CONCLUSION: This work demonstrates that phase changes resulting from variations in B0 due to drift and respiration, commonly seen in MR thermometry applications, can be measured directly from 3D Cartesian acquisition methods. The correction of temporal field variations using the presented technique improved temperature accuracy, reduced variability in nonheated regions, and did not reduce accuracy in heated regions.

DNA methylation in former extremely low birth weight newborns: association with cardiovascular and endocrine function.

BACKGROUND: There is increased risk of cardiovascular, metabolic, and hypertensive disorders in later life in the preterm population. We studied school-age children who had been born extremely premature who had undergone endocrine, cardiovascular, and anthropometric evaluations. METHODS: School age measurements of salivary cortisol, adrenal androgens, blood pressure, and anthropometric markers were correlated with DNA methylation of 11-betahydroxysteroid dehydrogenase type 2 (11BHSD2), leptin, and the LINE1 repetitive DNA element. RESULTS: We observed a modest correlation between log AUC for salivary cortisol and methylation of leptin in preterm infants and a negative correlation between methylation of region 1 of the glucocorticoid receptor (GR in term-born infants. There was an association between LINE1 methylation and cortisol response to awakening and a negative correlation between LINE1 and systolic blood pressure at 6-7 years. Methylation of the GR promoter region showed a positive association with systolic blood pressure at 6-7 years of age. CONCLUSIONS: These results show that extremely preterm birth, followed by complex patterns of endocrine, cardiovascular, and metabolic exposures during early postnatal life, is associated with lasting changes in DNA methylation patterns in genes involved in hypothalamic pituitary adrenal axis function, adrenal hormonal regulation, and cardiometabolic risk. IMPACT: Preterm infants have significant environmental and physiological exposures during early life that may have lasting impact on later function. Alterations in hypothalamic pituitary adrenal axis (HPA) function have been associated with these exposures. We examined the associated changes in DNA methylation of important genes involved in HPA function, metabolism, and global DNA methylation. The changes we saw in DNA methylation may help to explain associated cardiovascular, metabolic, and growth disturbance in these children in later life.

Flipping the Teachers: Impact of a Standardized Physiology Curriculum on Neonatology Medical Educators.

OBJECTIVE: Academic physicians must teach elements in an Accreditation Council for Graduate Medical Education (ACGME)-mandated curriculum while balancing career development and clinical workload. Exploring educator perceptions on the learning environment and comparing two instructional methods (traditional didactics [TD] vs. flipped classroom [FC]) in one pediatric subspecialty may elucidate current challenges, barriers, and strategies to optimize learning and educator satisfaction. STUDY DESIGN: A randomized trial comparing effectiveness and learner preference for FC versus TD physiology teaching was conducted in ACGME-accredited neonatal-perinatal medicine (NPM) fellowship programs in 2018 to 2019. Educator preferences were elicited through online surveys pre- and postintervention. Free-text comments were provided for questions exploring strengths, challenges, and opportunities in fellowship education. Statistical analysis included comparisons of demographics and pre-post-intervention educator responses between groups. Thematic analysis of text responses was conducted to identify common subthemes. RESULTS: From 61 participating programs, 114 FC educators and 130 TD educators completed surveys. At baseline, all educators experienced professional satisfaction from teaching fellows, but noted challenges with time available to create and/or deliver educational content, limited content expertise amongst faculty, colleagues' limited enthusiasm toward educating fellows, and lack of perceived value of education by institutions given limited protected time or credit toward promotion. Postintervention, educators in both groups noted a preference to teach physiology using FC due to interactivity, learner enthusiasm, and learner-centeredness. FC educators had a 17% increase in preference to teach using FC (p = 0.001). Challenges with FC included ensuring adequate trainee preparation, protecting educational time, and providing educators with opportunities to develop facilitation skills. CONCLUSION: Overall, NPM educators in a trial evaluating a standardized, peer-reviewed curriculum report professional satisfaction from teaching, but described logistical challenges with developing/delivering content. Educators preferred instruction using FC, but identified challenges with learner preparedness and ensuring adequate educator time and skill. Future efforts should be dedicated to addressing these barriers. KEY POINTS: · Many challenges exist for educators teaching neonatal-perinatal medicine fellows, including time, support, and recognition.. · Many educators preferred using flipped classroom methodology with a standardized curriculum due to interactivity and learner-centeredness.. · Benefits of a standardized, peer-reviewed curriculum include reduced preparation time, adaptability of content, and learning environment enhancement..

Experimental validation of acoustic and thermal modeling in heterogeneous phantoms using the hybrid angular spectrum method.

PURPOSE: The aim was to quantitatively validate the hybrid angular spectrum (HAS) algorithm, a rapid wave propagation technique for heterogeneous media, with both pressure and temperature measurements. METHODS: Heterogeneous tissue-mimicking phantoms were used to evaluate the accuracy of the HAS acoustic modeling algorithm in predicting pressure and thermal patterns. Acoustic properties of the phantom components were measured by a through-transmission technique while thermal properties were measured with a commercial probe. Numerical models of each heterogeneous phantom were segmented from 3D MR images. Cylindrical phantoms 30-mm thick were placed in the pre-focal field of a focused ultrasound beam and 2D pressure measurements obtained with a scanning hydrophone. Peak pressure, full width at half maximum, and normalized root mean squared difference (RMSDn) between the measured and simulated patterns were compared. MR-guided sonications were performed on 150-mm phantoms to obtain MR temperature measurements. Using HAS-predicted power density patterns, temperature simulations were performed. Experimental and simulated temperature patterns were directly compared using peak and mean temperature plots, RMSDn metrics, and accuracy of heating localization. RESULTS: The average difference between simulated and hydrophone-measured peak pressures was 9.0% with an RMSDn of 11.4%. Comparison of the experimental MRI-derived and simulated temperature patterns showed RMSDn values of 10.2% and 11.1% and distance differences between the centers of thermal mass of 2.0 and 2.2 mm. CONCLUSIONS: These results show that the computationally rapid hybrid angular spectrum method can predict pressure and temperature patterns in heterogeneous models, including uncertainties in property values and other parameters, to within approximately 10%.

Design and evaluation of an open-source, conformable skin-cooling system for body magnetic resonance guided focused ultrasound treatments.

PURPOSE: Magnetic resonance guided focused ultrasound (MRgFUS) treatment of tumors uses inter-sonication delays to allow heat to dissipate from the skin and other near-field tissues. Despite inter-sonication delays, treatment of tumors close to the skin risks skin burns. This work has designed and evaluated an open-source, conformable, skin-cooling system for body MRgFUS treatments to reduce skin burns and enable ablation closer to the skin. METHODS: A MR-compatible skin cooling system is described that features a conformable skin-cooling pad assembly with feedback control allowing continuous flow and pressure maintenance during the procedure. System performance was evaluated with hydrophone, phantom and in vivo porcine studies. Sonications were performed 10 and 5 mm from the skin surface under both control and forced convective skin-cooling conditions. 3D MR temperature imaging was acquired in real time and the accumulated thermal dose volume was measured. Gross analysis of the skin post-sonication was further performed. Device conformability was demonstrated at several body locations. RESULTS: Hydrophone studies demonstrated no beam aberration, but a 5-12% reduction of the peak pressure due to the presence of the skin-cooling pad assembly in the acoustic near field. Phantom evaluation demonstrated there is no MR temperature imaging precision reduction or any other artifacts present due to the coolant flow during MRgFUS sonication. The porcine studies demonstrated skin burns were reduced in size or eliminated when compared to the control condition. CONCLUSION: An open-source design of an MRgFUS active skin cooling system demonstrates device conformability with a reduction of skin burns while ablating superficial tissues.

Development and characterization of a tissue mimicking psyllium husk gelatin phantom for ultrasound and magnetic resonance imaging.

Purpose: To develop and characterize a tissue-mimicking phantom that enables the direct comparison of magnetic resonance (MR) and ultrasound (US) imaging techniques useful for monitoring high-intensity focused ultrasound (HIFU) treatments. With no additions, gelatin phantoms produce little if any scattering required for US imaging. This study characterizes the MR and US image characteristics as a function of psyllium husk concentration, which was added to increase US scattering.Methods: Gelatin phantoms were constructed with varying concentrations of psyllium husk. The effects of psyllium husk concentration on US B-mode and MR imaging were evaluated at nine different concentrations. T1, T2, and T2* MR maps were acquired. Acoustic properties (attenuation and speed of sound) were measured at frequencies of 0.6, 1.0, 1.8, and 3.0 MHz using a through-transmission technique. Phantom elastic properties were evaluated for both time and temperature dependence.Results: Ultrasound image echogenicity increased with increasing psyllium husk concentration while quality of gradient-recalled echo MR images decreased with increasing concentration. For all phantoms, the measured speed of sound ranged between 1567-1569 m/s and the attenuation ranged between 0.42-0.44 dB/(cm·MHz). Measured T1 ranged from 974-1051 ms. The T2 and T2* values ranged from 97-108 ms and 48-88 ms, respectively, with both showing a decreasing trend with increased psyllium husk concentration. Phantom stiffness, measured using US shear-wave speed measurements, increased with age and decreased with increasing temperature.Conclusions: The presented dual-use tissue-mimicking phantom is easy to manufacture and can be used to compare and evaluate US-guided and MR-guided HIFU imaging protocols.

Simultaneous proton resonance frequency shift thermometry and T1 measurements using a single reference variable flip angle T1 method.

PURPOSE: Implement simultaneous proton resonance frequency (PRF) shift and T1 measurements with equivalent temporal resolution using a single reference variable flip angle method. This novel method allows for simultaneous thermometry in both aqueous and fatty tissue. METHODS: This method acquires a single reference image at the lower flip angle and all dynamic images at the higher angle. T1 is calculated using a single reference variable flip angle method, which accounts for the reference image temperature remaining constant. Monte Carlo simulations determined the optimal dynamic flip angle for combined PRF and T1 measurements. This method was evaluated in MR-guided focused ultrasound heating experiments using a gelatin phantom and human cadaver breasts. In vivo measurement precision was demonstrated in healthy female volunteers under nonheating conditions. RESULTS: Temperature rise during MR-guided focused ultrasound heating was measured in aqueous tissue with both PRF and T1 . Both measures show good qualitative agreement in both space and time in aqueous tissue. The T1 change due to temperature increase was measured in fat, demonstrating the expected temporal response. The dynamic flip angle that produces optimal SNR for PRF measurements is lower than the optimal angle for T1 measurements, necessitating the selection of a compromise angle. CONCLUSION: The single reference variable flip angle method provides a reliable way to simultaneously measure PRF temperature and T1 change and overcomes PRF's inability to simultaneously monitor temperature in aqueous and adipose tissues. Future work will calibrate T1 change to temperature, enabling real-time temperature in fat and increasing patient safety and treatment efficacy during thermal interventional treatments.

Efficient shear wave elastography using transient acoustic radiation force excitations and MR displacement encoding.

PURPOSE: To present a novel MR shear wave elastography (MR-SWE) method that efficiently measures the speed of propagating wave packets generated using acoustic radiation force (ARF) impulses. METHODS: ARF impulses from a focused ultrasound (FUS) transducer were applied sequentially to a preselected set of positions and motion encoded MRI was used to acquire volumetric images of the propagating shear wavefront emanating from each point. The wavefront position at multiple propagation times was encoded in the MR phase image using a train of motion encoding gradient lobes. Generating a transient propagating wavefront at multiple spatial positions and sampling each at multiple time-points allowed for shear wave speed maps to be efficiently created. MR-SWE was evaluated in tissue mimicking phantoms and ex vivo bovine liver tissue before and after ablation. RESULTS: MR-SWE maps, covering an in-plane area of ~5 × 5 cm, were acquired in 12 s for a single slice and 144 s for a volumetric scan. MR-SWE detected inclusions of differing stiffness in a phantom experiment. In bovine liver, mean shear wave speed significantly increased from 1.65 ± 0.18 m/s in normal to 2.52 ± 0.18 m/s in ablated region (n = 581 pixels; P-value < 0.001). CONCLUSION: MR-SWE is an elastography technique that enables precise targeting and excitation of the desired tissue of interest. MR-SWE may be particularly well suited for treatment planning and endpoint assessment of MR-guided FUS procedures because the same device used for therapy can be used as an excitation source for tissue stiffness quantification.

Adrenal function links to early postnatal growth and blood pressure at age 6 in children born extremely preterm.

BACKGROUND: Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children. METHODS: Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30' later, evening). RESULTS: For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p < 0.01; girls p = 0.04). Cortisol was similar between preterm-born and term-born at study visit; however, preterm-born children showed a blunted morning cortisol. In term-born children, DHEA correlated with BMI (p = 0.04), subscapular, and abdominal skinfold thicknesses (both p < 0.01). CONCLUSION: Cortisol and DHEA correlated inversely with early postnatal growth and directly with systolic BP in extremely preterm-born children, suggesting perinatal programming. Blunted morning cortisol may reflect NICU stress, as seen after other adverse childhood experiences (ACEs).

Shared medical appointments and patient-centered experience: a mixed-methods systematic review.

BACKGROUND: Shared medical appointments (SMAs), or group visits, are a healthcare delivery method with the potential to improve chronic disease management and preventive care. In this review, we sought to better understand opportunities, barriers, and limitations to SMAs based on patient experience in the primary care context. METHODS: An experienced biomedical librarian conducted literature searches of PubMed, Cochrane Library, PsycINFO, CINAHL, Web of Science, ClinicalTrials.gov , and SSRN for peer-reviewed publications published 1997 or after. We searched grey literature, nonempirical reports, social science publications, and citations from published systematic reviews. The search yielded 1359 papers, including qualitative, quantitative, and mixed method studies. Categorization of the extracted data informed a thematic synthesis. We did not perform a formal meta-analysis. RESULTS: Screening and quality assessment yielded 13 quantitative controlled trials, 11 qualitative papers, and two mixed methods studies that met inclusion criteria. We identified three consistent models of care: cooperative health care clinic (five articles), shared medical appointment / group visit (10 articles) and group prenatal care / CenteringPregnancy® (11 articles). CONCLUSIONS: SMAs in a variety of formats are increasingly employed in primary care settings, with no singular gold standard. Accepting and implementing this nontraditional approach by both patients and clinicians can yield measurable improvements in patient trust, patient perception of quality of care and quality of life, and relevant biophysical measurements of clinical parameters. Further refinement of this healthcare delivery model will be best driven by standardizing measures of patient satisfaction and clinical outcomes.

Communal schools and teacher victimization.

Despite data showing that teacher victimization is at least as great a problem as student victimization, far less research exists regarding teacher victimization than student victimization and overall school crime, particularly with regard to the application of criminological theory to explain the victimization of teachers. We address this gap by examining the hierarchical relationship between communal school organization and teacher victimization in a nationally representative sample of 37,497 teachers from 7,488 public schools in the United States. Results showed that teacher experienced less victimization in schools that were more communally organized. We discuss these findings and present implications for school-based delinquency prevention.

Multiecho pseudo-golden angle stack of stars thermometry with high spatial and temporal resolution using k-space weighted image contrast.

PURPOSE: Implement and evaluate a 3D MRI method to measure temperature changes with high spatial and temporal resolution and large field of view. METHODS: A multiecho pseudo-golden angle stack-of-stars (SOS) sequence with k-space weighted image contrast (KWIC) reconstruction was implemented to simultaneously measure multiple quantities, including temperature, initial signal magnitude M(0), transverse relaxation time ( T2*), and water/fat images. Respiration artifacts were corrected using self-navigation. KWIC artifacts were removed using a multi-baseline library. The phases of the multiple echo images were combined to improve proton resonance frequency precision. Temperature precision was tested through in vivo breast imaging (N = 5 healthy volunteers) using both coronal and sagittal orientations and with focused ultrasound (FUS) heating in a pork phantom using a breast specific MR-guided FUS system. RESULTS: Temperature measurement precision was significantly improved after echo combination when compared with the no echo combination case (spatial average of the standard deviation through time of 0.3-1.0 and 0.7-1.9°C, respectively). Temperature measurement accuracy during heating was comparable to a 3D seg-EPI sequence. M(0) and T2* values showed temperature dependence during heating in pork adipose tissue. CONCLUSION: A self-navigated 3D multiecho SOS sequence with dynamic KWIC reconstruction is a promising thermometry method that provides multiple temperature sensitive quantitative values. Magn Reson Med 79:1407-1419, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Validation of hybrid angular spectrum acoustic and thermal modelling in phantoms.

In focused ultrasound (FUS) thermal ablation of diseased tissue, acoustic beam and thermal simulations enable treatment planning and optimization. In this study, a treatment-planning methodology that uses the hybrid angular spectrum (HAS) method and the Pennes' bioheat equation (PBHE) is experimentally validated in homogeneous tissue-mimicking phantoms. Simulated three-dimensional temperature profiles are compared to volumetric MR thermometry imaging (MRTI) of FUS sonications in the phantoms, whose acoustic and thermal properties are independently measured. Additionally, Monte Carlo (MC) uncertainty analysis is performed to quantify the effect of tissue property uncertainties on simulation results. The mean error between simulated and experimental spatiotemporal peak temperature rise was +0.33°C (+6.9%). Despite this error, the experimental temperature rise fell within the expected uncertainty of the simulation, as determined by the MC analysis. The average errors of the simulated transverse and longitudinal full width half maximum (FWHM) of the profiles were -1.9% and 7.5%, respectively. A linear regression and local sensitivity analysis revealed that simulated temperature amplitude is more sensitive to uncertainties in simulation inputs than in the profile width and shape. Acoustic power, acoustic attenuation and thermal conductivity had the greatest impact on peak temperature rise uncertainty; thermal conductivity and volumetric heat capacity had the greatest impact on FWHM uncertainty. This study validates that using the HAS and PBHE method can adequately predict temperature profiles from single sonications in homogeneous media. Further, it informs the need to accurately measure or predict patient-specific properties for improved treatment planning of ablative FUS surgeries.

Thermal diffusivity and perfusion constants from in vivo MR-guided focussed ultrasound treatments: a feasibility study.

PURPOSE: This study investigates the feasibility of non-invasively determining thermal diffusivity (α) and the Pennes perfusion parameter (w) from pre-clinical and clinical magnetic resonance-guided focussed ultrasound (MRgFUS) temperature data. MATERIALS AND METHODS: Pre-clinical MRgFUS experiments were performed in rabbit muscle (N = 3, 28 sonications) using three-dimensional MR thermometry. Eight sonications were made in a clinical QA phantom with two-dimensional thermometry. Retrospective property determination was performed on clinical uterine fibroid (N = 8, 9 sonications) and desmoid tumour (N = 4, 7 sonications) data. The property determination method fits an analytical solution to MRgFUS temperatures in the coronal MR plane, including all temperatures acquired during heating and one cooling image. When possible, additional cooling data were acquired for property determination. RESULTS: Rabbit α and w from Heating Data (α = 0.164 mm2s-1, w = 7.9 kg m-3 s-1) and Heating and Cooling Data (α = 0.146 mm2s-1, w = 3.3 kg m-3 s-1) were within the range of gold-standard invasive measurements, with >50% reduction in variability by including cooling data. QA phantom property determination with cooling data yielded properties within 3% of expected values (α = 0.144 mm2s-1, w = 0.0 kg m-3 s-1), a difference that was not statistically significant (p = 0.053). Uterine fibroid (Heating Data: α = 0.212 mm2s-1, w = 11.0 kg m-3 s-1) and desmoid tumour (Heating & Cooling Data: α = 0.245 mm2s-1, w = 4.7 kg m-3 s-1) properties are feasible but lack independent verification. CONCLUSIONS: Thermal diffusivity and the Pennes perfusion parameter can be obtained from in vivo data and with clinical MRgFUS protocols. Property values are consistently improved by including cooling data. The utility of this property determination method will increase as clinical protocols implement improved temperature imaging.

Experimental assessment of phase aberration correction for breast MRgFUS therapy.

PURPOSE: This study validates that phase aberrations in breast magnetic resonance-guided focussed ultrasound (MRgFUS) therapies can be corrected in a clinically relevant time frame to generate more intense, smaller and more spatially accurate foci. MATERIALS AND METHODS: Hybrid angular spectrum (HAS) ultrasound calculations in an magnetic resonance imaging (MRI)-based tissue model, were used to compute phase aberration corrections for improved experimental MRgFUS heating in four heterogeneous breast-mimicking phantoms (n = 18 total locations). Magnetic resonance(MR) temperature imaging was used to evaluate the maximum temperature rise, focus volume and focus accuracy for uncorrected and phase aberration-corrected sonications. Thermal simulations assessed the effectiveness of the phase aberration correction implementation. RESULTS: In 13 of 18 locations, the maximum temperature rise increased by an average of 30%, focus volume was reduced by 40% and focus accuracy improved from 4.6 to 3.6 mm. Mixed results were observed in five of the 18 locations, with focus accuracy improving from 6.1 to 2.5 mm and the maximum temperature rise decreasing by 8% and focus volume increasing by 10%. Overall, the study demonstrated significant improvements (p < 0.005) in maximum temperature rise, focus volume and focus accuracy. Simulations predicted greater improvements than observed experimentally, suggesting potential for improvement in implementing the technique. The complete phase aberration correction procedure, including model generation, segmentation and phase aberration computations, required less than 45 min per sonication location. CONCLUSION: The significant improvements demonstrated in this study i.e., focus intensity, size and accuracy from phase aberration correction have the potential to improve the efficacy, time-efficiency and safety of breast MRgFUS therapies.

Focal point determination in magnetic resonance-guided focused ultrasound using tracking coils.

PURPOSE: To develop a method for rapid prediction of the geometric focus location in MR coordinates of a focused ultrasound (US) transducer with arbitrary position and orientation without sonicating. METHODS: Three small tracker coil circuits were designed, constructed, attached to the transducer housing of a breast-specific MR-guided focused US (MRgFUS) system with 5 degrees of freedom, and connected to receiver channel inputs of an MRI scanner. A one-dimensional sequence applied in three orthogonal directions determined the position of each tracker, which was then corrected for gradient nonlinearity. In a calibration step, low-level heating located the US focus in one transducer position orientation where the tracker positions were also known. Subsequent US focus locations were determined from the isometric transformation of the trackers. The accuracy of this method was verified by comparing the tracking coil predictions to thermal center of mass calculated using MR thermometry data acquired at 16 different transducer positions for MRgFUS sonications in a homogeneous gelatin phantom. RESULTS: The tracker coil predicted focus was an average distance of 2.1 ± 1.1 mm from the thermal center of mass. The one-dimensional locator sequence and prediction calculations took less than 1 s to perform. CONCLUSION: This technique accurately predicts the geometric focus for a transducer with arbitrary position and orientation without sonicating. Magn Reson Med 77:2424-2430, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Enhanced efficacy of combination heat shock targeted polymer therapeutics with high intensity focused ultrasound.

Combination of polymer therapeutics and hyperthermia has been shown to enhance accumulation in selectively heated tumor tissue. The additional use of heat shock (HS)-targeting towards tumor tissues can further enhance accumulation and retention, and improve therapeutic outcomes. In this work, high intensity focused ultrasound (HIFU) was used to generate hyperthermia in prostate tumor tissue. Upregulation of the cell surface HS receptor glucose regulated protein 78 kDa (GRP78) was observed after treatment with HIFU hyperthermia which was then targeted by specific HS-targeting peptides. We used the peptide sequence WDLAWMFRLPVG attached to the side chains of water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing docetaxel (DOC) conjugated via a lysosomally degradable linker. It was shown that HIFU-mediated HS-targeted copolymer-DOC conjugates improved treatment efficacy in a murine prostate tumor xenograft model. These results show that the use of HIFU hyperthermia in combination with HS-targeted polymer-drug conjugates has potential to improve therapeutic outcomes in prostate cancer treatment.